IP Library › Granted Patent US 12,285,462
Granted Patent B2
US 12,285,462 · App. 18/325,884 · Granted Apr 29, 2025

pH-triggered membrane peptide-mediated epitope tethering at cell surfaces

Inventors: Yana K. Reshetnyak (Saunderstown, RI); Oleg A. Andreev (Saunderstown, RI); Anna Moshnikova (Warwick, RI); Donald M. Engelman (New Haven, CT)
Assignees: University of Rhode Island Board of Trustees; Yale University
A61K38/16A61K38/195A61K38/20A61K45/05A61K47/00A61K47/10A61K2121/00C07K2319/33
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,285,462
App. No.
18/325,884
Granted
Apr 29, 2025
Kind
B2
Abstract

The invention features methods and compositions for eliciting an anti-tumor response in a subject comprising administering to the subject a pHLIP ● construct comprising an antibody recruiting molecule linked to one or more pHLIP ● peptides by a non-cleavable linker compound. The construct increases the amount of the antibody recruiting molecule on the surface of a diseased cell.

Claims (18)

1. A composition comprising an epitope linked to one or more pH-triggered peptides by a non-cleavable linker compound, wherein the composition comprises the formula of Epitope-Linker-Peptide, wherein Epitope is an antibody recruiting molecule or immune cell recruiting molecule, wherein Linker is a linker or an extension of the pH-triggered peptide, wherein Peptide is a pH-triggered peptide comprising the sequence AXDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 18) or AXDQDNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 495), wherein upper case “X” indicates any amino acid or an Azido-containing amino acid, wherein each is a covalent bond, and wherein Epitope is a hemagglutinin peptide (HA peptide) and comprises a length of less than 50 amino acids.

2. The composition of claim 1 , wherein two Epitopes are linked to a single pH-triggered peptide.

3. The composition of claim 1 , wherein the HA peptide comprises the amino acid sequence of YPYDVPDYA (SEQ ID NO: 6).

4. The composition of claim 1 , wherein the linker is a polyethylene glycol (PEG) linker ranging from 12 to 24 PEG units.

5. A composition comprising two antibody recruiting molecules linked to a pH-triggered peptide, wherein the composition comprises the formula of Epitope1-Linker-Peptide-Linker-Epitope1, wherein Epitope1 is an antibody recruiting molecule; wherein Linker is a PEG linker; wherein Peptide is a pH-triggered peptide comprising the sequence Ac-AKQNDDQNKPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 511); Ac-AKQNDNDNKPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 535); ACQNDDQNCPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 536); or ACQNDNDNCPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 505), wherein each-is a covalent bond, and wherein one or both of the Epitope1 is a hemagglutinin peptide (HA peptide) and comprises a length of less than 50 amino acids.

6. The composition of claim 5 , wherein the HA peptide comprises the amino acid sequence of YPYDVPDYA (SEQ ID NO: 6).

7. The composition of claim 5 , wherein one or both of the Epitopel is selected from the group consisting of QVSHWVSGLAEGSFG (SEQ ID NO: 1), LSHTSGRVEGSVSLL (SEQ ID NO: 2), QMWAPQWGPD (SEQ ID NO: 3); MASMTGGQQMG (SEQ ID NO: 4); EQKLISEEDL (SEQ ID NO: 5); YTDIEMNRLGK (SEQ ID NO: 7); KETAAAKFERQHMDS (SEQ ID NO: 8); GKPIPNPLLGLDST (SEQ ID NO: 9); DYKDDDDK (SEQ ID NO: 10); GAPVPYPDPLEPR (SEQ ID NO: 11); HHHHHH (SEQ ID NO: 12); TKENPRSNQEESYDDNES (SEQ ID NO: 13); WSHPQFEK (SEQ ID NO: 14); and PDRVRAVSHWSS (SEQ ID NO: 15).

8. The composition of claim 5 , wherein the PEG linker ranges from 12 to 24 PEG units.

9. The composition of claim 1 , wherein the composition is formulated with a pharmaceutically acceptable carrier.

10. The composition of claim 1 , wherein the composition is for intravenous, subcutaneous, intraarterial, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intracardiac, intracavernous, intraosseous, intraocular, intravitreal, intramuscular, intradermal, transdermal, transmucosal, intralesional, topical, epicutaneous, extra-amniotic, intravaginal, intravesical, nasal, or oral administration.

11. The composition of claim 1 , wherein the composition is for direct injection into a diseased tissue.

12. The composition of claim 11 , wherein the composition preferentially targets diseased tissue compared to a healthy tissue, thereby minimizing damage to the healthy tissue.

13. The composition of claim 12 , wherein the diseased tissue is a tumor or an inflamed tissue.

14. The composition of claim 5 , wherein the composition is formulated with a pharmaceutically acceptable carrier.

15. The composition of claim 5 , wherein the composition is for intravenous, subcutaneous, intraarterial, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intracardiac, intracavernous, intraosseous, intraocular, intravitreal, intramuscular, intradermal, transdermal, transmucosal, intralesional, topical, epicutaneous, extra-amniotic, intravaginal, intravesical, nasal, or oral administration.

16. The composition of claim 5 , wherein the composition is for direct injection into a diseased tissue.

17. The composition of claim 16 , wherein the composition preferentially targets diseased tissue compared to a healthy tissue, thereby minimizing damage to the healthy tissue.

18. The composition of claim 17 , wherein the diseased tissue is a tumor or an inflamed tissue.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2025
From: RESHETNYAK, YANA K.; ANDREEV, OLEG A.; MOSHNIKOVA, ANNA
To: UNIVERSITY OF RHODE ISLAND BOARD OF TRUSTEES
Reel/Frame 070007/0338 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2025
From: ENGELMAN, DONALD M.
To: YALE UNIVERSITY
Reel/Frame 070007/0353 →
CONFIRMATORY LICENSE Recorded Jan 24, 2024
From: UNIVERSITY OF RHODE ISLAND
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 066369/0530 →
Continuity (3)
Continuation 16775113 · Jan 28, 2020
Provisional Application 62797899 · Jan 28, 2019
Related Publication 20240066096A1 · Feb 29, 2024
References Cited (97)
US 8076451B2 · Reshetnyak et al. · 2011 [cited by applicant]
US 8703909B2 · Reshetnyak et al. · 2014 [cited by applicant]
US 8846081B2 · Reshetnyak et al. · 2014 [cited by applicant]
US 9289508B2 · Reshetnyak et al. · 2016 [cited by applicant]
US 9676823B2 · Reshetnyak et al. · 2017 [cited by applicant]
US 9750693B2 · Reshetnyak et al. · 2017 [cited by applicant]
US 9814781B2 · Reshetnyak et al. · 2017 [cited by applicant]
US 10512606B2 · Reshetnyak et al. · 2019 [cited by applicant]
US 11229710B2 · Reshetnyak et al. · 2022 [cited by applicant]
US 11267853B2 · Reshetnyak et al. · 2022 [cited by applicant]
US 11274126B2 · Reshetnyak et al. · 2022 [cited by applicant]
US 11738096B2 · Reshetnyak et al. · 2023 [cited by applicant]
US 11779662B2 · Reshetnyak et al. · 2023 [cited by applicant]
US 11857509B2 · Reshetnyak et al. · 2024 [cited by applicant]
US 12029793B2 · Reshetnyak et al. · 2024 [cited by applicant]
US 20070160571A1 · Krathwohl · 2007 [cited by applicant]
US 20080233107A1 · Reshetnyak · 2008 [cited by examiner]
US 20120039990A1 · Reshetnyak et al. · 2012 [cited by applicant]
US 20120142042A1 · Reshetnyak et al. · 2012 [cited by applicant]
US 20130136763A1 · Song · 2013 [cited by examiner]
US 20150051153A1 · Reshetnyak et al. · 2015 [cited by applicant]
US 20150086617A1 · Reshetnyak et al. · 2015 [cited by applicant]
US 20150190471A1 · Copik · 2015 [cited by examiner]
US 20150191508A1 · Reshetnyak et al. · 2015 [cited by applicant]
US 20160229901A1 · Merchant · 2016 [cited by applicant]
US 20160256560A1 · Reshetnyak et al. · 2016 [cited by applicant]
US 20180057594A1 · Evnin · 2018 [cited by applicant]
US 20180064648A1 · Reshetnyak et al. · 2018 [cited by applicant]
US 20180117183A1 · Reshetnyak · 2018 [cited by examiner]
US 20180221500A1 · Reshetnyak et al. · 2018 [cited by applicant]
US 20180369425A1 · Reshetnyak et al. · 2018 [cited by applicant]
US 20190231904A1 · Reshetnyak et al. · 2019 [cited by applicant]
US 20190382448A1 · Reshetnyak et al. · 2019 [cited by applicant]
US 20200237926A1 · Reshetnyak et al. · 2020 [cited by applicant]
US 20200246420A1 · Reshetnyak et al. · 2020 [cited by applicant]
US 20200253872A1 · Reshetnyak et al. · 2020 [cited by applicant]
US 20200262881A1 · Reshetnyak et al. · 2020 [cited by applicant]
US 20200323882A1 · Reshetnyak et al. · 2020 [cited by applicant]
US 20220088208A1 · Reshetnyak et al. · 2022 [cited by applicant]
US 20220281919A1 · Reshetnyak et al. · 2022 [cited by applicant]
US 20240042063A1 · Reshetnyak et al. · 2024 [cited by applicant]
US 20240075170A1 · Reshetnyak et al. · 2024 [cited by applicant]
US 20240148911A1 · Reshetnyak et al. · 2024 [cited by applicant]
US 20240173258A1 · Reshetnyak et al. · 2024 [cited by applicant]
WO WO2006078816A2 · 2006 [cited by applicant]
WO WO2012021790A1 · 2012 [cited by applicant]
WO WO2012047354A2 · 2012 [cited by applicant]
WO WO2017165452A1 · 2017 [cited by applicant]
WO WO2018057912A1 · 2018 [cited by applicant]
WO WO2018227132A1 · 2018 [cited by applicant]
WO WO2020159983A1 · 2020 [cited by applicant]
WO WO2020160009A1 · 2020 [cited by applicant]
WO WO2020160031A1 · 2020 [cited by applicant]
WO WO2020160047A2 · 2020 [cited by applicant]
WO WO2020190733A1 · 2020 [cited by applicant]
WO WO2024040027A2 · 2024 [cited by applicant]
Altschul et al., “Basic Local Alignment Search Tool,” J. Mol. Biol. 215:403-410 (1990). [cited by applicant]
Altschul et al., “Gapped BLAST and PSI-BLAST: A New Generation of Protein Database Search Programs,” Nucl. Acids Res. 25(17):3389-3402 (1997). [cited by applicant]
Database Genebank, “Interleukin-6 Isoform 1 Precursor [ [cited by applicant]
Genebank, “C-X-C Motif Chemokine 10 Precursor [ [cited by applicant]
Genebank, “C-X-C Motif Chemikine 11 Isoform 1 Precursor [ [cited by applicant]
Genebank, “C-X-C Motif Chemokine 9 Precursor [ [cited by applicant]
Genebank, “Frractalkine Isoform 1 Precursor [ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “ [cited by applicant]
Genebank, “Interleukin 2 [ [cited by applicant]
Genebank, “Interleukin-7 Isoform 1 Precursor [ [cited by applicant]
Genbank, “Receptor tyrosine-protein kinase erbB-2 isoform b [ [cited by applicant]
Genbank, “Tumor Necrosis Factor [ [cited by applicant]
Henikoff et al., “Amino Acid Substitution Matrices from Protein Blocks,” PNAS USA 89(22):10915-10919 (Nov. 15, 1992). [cited by applicant]
Krause et al., “Tyrosine Kinases as Targets for Cancer Therapy,” New England Journal of Medicine 353(2):172-187 (Jul. 14, 2005). [cited by applicant]
Needleman et al., “A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins,” J. Mol. Biol. 48(3):443-342 (Mar. 28, 1970). [cited by applicant]
Pearson et al., “Improved Tools for Biological Sequence Comparison,” PNAS 85:2444-2448 (Apr. 1988). [cited by applicant]
Smith et al., “Comparison of Biosequences,” Adv. Appl. Math. 2(4):482-489 (Dec. 1981). [cited by applicant]
Uniprot, “Interleukin-12 Subunit Alpha,” Accession No. P29459 (Apr. 1, 1993). [cited by applicant]
Uniprot, “Interleukin-12 Subunit Beta,” Accession No. P29460 (Apr. 1, 1993). [cited by applicant]
Weerakkody et al., “Family of pH (low) insertion peptides for tumor targeting,” PNAS 110(15):5834-5839 (Apr. 9, 2013). [cited by applicant]
Office Action mailed Feb. 9, 2022, in U.S. Appl. No. 16/775,113, Reshetnyak et al., filed Jan. 28, 2020, 13 pages. [cited by applicant]
Office Action mailed Sep. 7, 2022, in U.S. Appl. No. 16/775,113, Reshetnyak et al., filed Jan. 28, 2020, 11 pages. [cited by applicant]
Office Action mailed Feb. 27, 2023, in U.S. Appl. No. 16/775,113, Reshetnyak et al., filed Jan. 28, 2020, 21 pages. [cited by applicant]
Jung et al., “Impact of Hapten Presentation on Antibody Binding at Lipid Membrane Interfaces,” Biophysical Journal, Apr. 15, 2008, 84(8):P3094-3103. [cited by applicant]
Muenchmeier et al., “A Novel CXCL10-Based GPI-Anchored Fusion Protein as Adjuvant in NK-Based Tumor Therapy,” Plos One, Aug. 30, 2013, 8(8):e72749. [cited by applicant]
McEnaney et al., “Antibody-Recruiting Molecules: An Emerging Paradigm for Engaging Immune Function in Treating Human Disease,” ACS Chemical Biology, Jul. 20, 2012, 7(7):1139-1151. [cited by applicant]
Co-pending U.S. Appl. No. 18/499,655, inventors: Reshetnyak et al., filed Nov. 1, 2023 (Not Published). [cited by applicant]
Co-pending U.S. Appl. No. 18/349,851, inventors: Reshetnyak et al., filed Jul. 10, 2023 (Not Published). [cited by applicant]
Co-pending U.S. Appl. No. 18/349,855, inventors: Reshetnyak et al., filed Jul. 10, 2023 (Not Published). [cited by applicant]
Co-pending U.S. Appl. No. 18/608,699, inventors: Reshetnyak et al., filed Mar. 18, 2024 (Not Published). [cited by applicant]
International Search Report and Written Opinion corresponding to International Patent Application No. PCT/US2017/023458, ISA/US, United States, mailed Aug. 25, 2017, 21 pages. [cited by applicant]
Krause et al., “Epitopes Expressed in Different Adenovirus Capsid Proteins Induce Different Levels of Epitope-Specific Immunity,” Journal of Virology, Jun. 2006, 80(11): 5523-5530. [cited by applicant]